Abstract A major challenge in HIV research is to restore immune function in HIV-infected individuals. HIV infection causes CD4 T cell depletion, leading to immunodeficiency and death. HAART induces restoration of CD4 T cell counts to normal levels in a majority of individuals who achieve durable virologic suppression. However, the magnitude of CD4 T cell recovery and is variable and a significant subset of individuals who achieve virologic suppression on HAART have poor CD4 T cell recovery. Unique challenges in drug abusing populations include the difficulty of achieving consistent adherence to HAART in individuals who are actively abusing drugs or have demographic characteristics that adversely influence health care access. Furthermore, drug abuse and HCV co-infection may influence responses to HAART. The overall goal of this proposal is to understand mechanisms that lead to recovery of immune function in HIV-infected individuals who achieve durable virologic suppression following HAART initiation. The working hypothesis is that individuals who achieve durable virologic suppression and good CD4 T cell recovery following HAART initiation have a coordinated pattern of epigenetic modification in CD4 T cells that is altered and leads to CD4 T cell dysfunction in individuals who have poor CD4 T cell recovery. We will use systems biology approaches to identify early epigenetic signatures that predict restoration of CD4 T cells in HIV-infected individuals from the MACS and ALIVE cohorts following initiation of successful HAART. Epigenetic mapping data will be integrated with clinical data, gene expression profiling, and mechanistic studies to better understand relationships between early epigenetic signatures, disease markers, and underlying mechanisms. The studies will lead to a better understanding of mechanisms that determine CD4 T cell restoration in IV drug abusers and other at-risk populations infected with HIV and may identify new therapeutic strategies to improve restoration of CD4 T cells in these populations.